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Patented Sept. 27, 1949 UNITED STATE PRODUCTION OF NEW DERIVATIVES OFPYRIDINE-3-CARBOXYLIC ACID Hans Suter, Schafihausen, Switzerland,assignor to Cilag Limited, Schaiihausen, Switzerland N Drawing.Application August 31, 1946, Serial in which R1 and R2 denote hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, dialkylaminoalkyl, aryl,aralkyl, hydroxyaryl, alkoxyaryl, hydroxyaralkyl or alkoxyaralkyl,radicals or R1 and R2 denote together a single bivalent radical of analkane, alkyl ether, alkyl amine, dialkyl amine, aralkane, aralkanol,aralkyl amine, hydroxyaralkane or alkoxyaralkane. The compounds of thisgeneral formula have proved to be valuable therapeutic substances. Theyhave, inter alia, good spasmolytic properties and are to be employedespecially for suppressing neurogenic and myogenic spasms.

The invention also covers the aforesaid new compounds.

The process for the production of these new derivatives ofpyridine-3-carboxylic acid is characterized by the feature that acompound, which contains the radical of nicotinic acid, e. g., nicotim'cacid, its anhydride, a nicotinyl halide or an ester of nicotinic acid,is caused to act up an amine of the general formula in which R1 and R2have the meaning given above, the nicotinamide corresponding to theamine being formed. Especially efiicacious compounds are obtained byemploying the following amines: amino diphenylmethane, amino cal?diphenylethane, a-amino-B-hydroxy-a d-diphenybethane,tetrahydro-[i-naphthylamine, 1-amino-acenaphthene,l-hydroxy-2-amino-acenaphthene, aminol:1'- diphenyl- 2:2'- 05,,6-ethane, a-amino- ,8- hydroxy- 1:1-diphenyl-2:2-a,B-ethane, ill-amino-9:lG-dihydroanthracene, 9-hyclroxy 10-an1inc- 9: 10-dihydroanthraceneand 9-amino-fluorene.

Example 1 51.1 gms. of freshly calcined potassium carbonate are added,slowly and while stirring, to 32.? gms. of nicotinyl chloridehydrochloride and 42 gms. of aminodiphenylmethane in 250 cos. ofabsolute benzene. The mixture is boiled for 9 hours under the refluxcondenser and the undissolved matter is filtered ofi and recrystallisedIn Switzerland September 15,.

. 2 from ethanol. Yields 57.3 gms. 86.4% of the theoretical. Thenicotinyl amino diphenylmethane obtained in this way crystallises incolourless needles which melt at 175-180 C. It is 5 readily soluble inchloroform, acetone and methanol, moderately soluble in ethanol,slightly soluble in benzene and ether and insoluble in water.

Example 2 A mixture of 36 gms. of nicotinic acid and 57.5 gms. ofamino-a,;3-diphenyl-ethane in 300 ccs. of cumene is heated at itsboiling point, so that cumene and the water formed in the reactiondistil slowly into a receiver which allows the volume of the distillateto be measured. As soon as the bottom aqueous layer amounts to 5.2 cos,the remaining cumene is distilled ofi in vacuo and the residue, whichconsists of nicotyl-amino-w,fldiphenyl-ethane, is recrystallised fromethanol. The new compound forms colourless clusters of needle-shapedcrystals having a melting point of 159 C. It is readily soluble in 5N-hydrochloric acid, moderately soluble in methanol, acetone, ether andbenzene, slightly soluble in ethanol and insoluble in water and inalkalis.

Example 3 44.35 gms. of freshly calcined potassium carbonate are addedto a mixture of 28.44 gms. of nicotinyl chloride hydrochloride, 34.23gms. oz-

amino-18-hydroXy-u,,B-diphenyl-ethane and 200 cos. of absolute alcohol.The whole is boiled for 11 hours under the reflux condenser and, then,after cooling, the undissolved matter is filtered off and recrystallisedfrom ethanol. u-nicotinylamino-,c-hydroxy-afi-diphenyl-ethane areobtained in this way in colourless needles having a melting point of 223C. The new compound is readily soluble in acetone and pyridine, slightlysoluble in ether, benzene, glacial acetic acid and ethanol and insolublein water.

E sample 4 17 gms. of nicotinic acid, 20 gms. of tetrahydro-B-naphthylamine and 100 cos. of xylene are heated together so that waterproduced in the reaction a small quantity of xylene distil ofi. After2.4 gms. of water have collected in the receiver, the remainder isevaporated to dryness in vacuo and the residue is recrystallised fromethanol. so The nicotinyl-tetrahydro-B-naphthylamide which is obtainedin this way crystallises in colourless, small plates which melt at 154C. Yield:28.9 gms. corresponding to 77.6% of the theoretical. The newamide is readily soluble in acetone, chloroform and pyridine, slightlysoluble in ethanol and insoluble in water.

3 4 What I claim is: 1. As a medicinal substance, nicotinylamino-REFERENCES CITED 5 i h 1 th of t formula, The following references areof record in the file of this patent: 0 UNITED STATES PATENTS NumberName Date N Q 1,617,332 Hartman Feb. 15, 1927 2. A process for theproduction of nicotinyl- 10 FOREIGN PATENTS amino-mfi-diphenyl-ethanecomprising reacting Number Country t a compound selected from the groupconsisting of 539 17 Germany 12 1931 nicotinic acid, its anhydride and anicotinyl halide, with amino-a, 3-diphenyl-ethane of the formula OTHERREFERENCES 'Machek: Monatshefte fiir Chemie, vol. 72, pp.

HzN-GH-O 15 s1, s2, s3, 91.

HANS SUI'ER.

